Pacing configuration for an implantable medical device

ABSTRACT

An implantable medical device includes a sensor configured to generate an endocardial acceleration (EA) signal representative of activity of a patient&#39;s heart. The device further includes one or more circuits configured to identify within the EA signal at least one EA signal component corresponding to at least one peak of endocardial acceleration, and extract from the at least one EA signal component at least two characteristic parameters. The one or more circuits are further configured to generate a composite index based on a combination of the at least two characteristic parameters, determine a plurality of values of the composite index for a plurality of pacing configurations, and select a current pacing configuration from among the plurality of pacing configurations based on the plurality of values of the composite index.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/263,643, filed Apr. 28, 2014, which is a continuation of U.S. patentapplication Ser. No. 13/411,412, filed Mar. 2, 2012, which claims thebenefit of and priority to French Patent Application No. 1151729, filedMar. 3, 2011, all of which are hereby incorporated by reference hereinin their entireties.

BACKGROUND

The present invention relates to “active implantable medical devices” asdefined by the 20 Jun. 1990 Directive 90/385/EEC of the Council of theEuropean Communities, and more particularly to those devices thatcontinuously monitor a patient's heart rhythm and deliver to the heart,if necessary, electrical pulses for joint and permanent stimulation ofthe left and the right ventricles, so as to resynchronize them, saidtechnique being known as Cardiac Resynchronization Therapy (“CRT”) orBi-Ventricular Pacing (“BVP”).

Cardiac resynchronization is known whereby a patient is implanted with adevice equipped with electrodes to stimulate various sites in bothventricles (often called a CRT device or CRT pacemaker). The CRT devicetypically applies between the respective moments of stimulation of theleft and right ventricles a delay that is called an “interventriculardelay” (VVD) which VVD is adjusted to resynchronize the contraction ofboth ventricles to optimize the patient's hemodynamic status.

A CRT pacemaker is for example disclosed in EP 1108446 A1 and itscounterpart U.S. Pat. No. 6,556,866 (both assigned to Sorin CRM S.A.S.,previously known as ELA Medical), which describes a CRT device forapplying between the two ventricular pacing sites a variable VVD,adjusted to resynchronize the contractions of the ventricles with a fineoptimization of the patient's hemodynamic status. The VVD may be zero(meaning that the left and right ventricles are stimulated essentiallysimultaneously), positive (meaning that the left ventricle is stimulatedafter the right ventricle) or negative (meaning that the right ventricleis stimulated after the left ventricle).

Clinical studies have often observed a dramatic improvement in resultsfor patients diagnosed with heart failure that is not improved byconventional therapy, because the parameters of the CRT therapy havebeen precisely adjusted according to the patient and to the nature ofthe patient's disorder.

But the implementation of CRT devices remains a very delicateintervention for the practitioner, because of the many choices that mustbe made. First, it must be determined for each of the leads the beststimulation site. The physical locations of the pacing electrodes foreach lead relative to the myocardial tissue are called “pacing sites”;generally, these pacing sites can only be selected at implantation, byappropriate positioning of the electrodes. It is important to verify theeffectiveness of the selected pacing sites, due to the possibleinfluence of long-term efficacy of the resynchronization therapy. Insome cases, the CRT device has several multi-site electrodes placed inthe same cavity, and a change of pacing site(s) for deliveringstimulation pulses in this cavity is possible by internal switching ofthe device.

In any case, during the intervention, the practitioner tests severalpossible pacing sites by successive repositioning of the lead to findthe one that he believes is the most appropriate.

Another aspect of the development of these CRT devices is the increasingnumber of electrodes, especially for “multisite” devices that allowselecting the pacing sites used for the delivery of stimulation pulsesand detection of myocardial potentials (e.g., from spontaneous cardiacevents) and optimizing the operation of the CRT device.

The increasing number of electrodes can also result from the presence atthe same level of the lead of several sectorial electrodes (electrodesspecifically directed in a radial direction relative to the lead, at thepacing site), with the possibility to select one or the other of thesesectorial electrodes to optimize the delivery of pulses to the selectedpacing site. This is particularly true for leads implanted in thecoronary venous system, for indirect stimulation of a left cavity: withseveral sectorial electrodes, it is possible to select one that isturned towards the epicardium wall facing the cavity in contact withthis wall.

Second, with the development of implantable medical devices forstimulation of more than two ventricular sites, it is necessary todetermine whether this * * * “tri-ventricular” or “multi-ventricular”mode of stimulation is or is not preferable to a conventional“bi-ventricular” pacing mode.

Thus, the practitioner may be faced with a choice between a standardmode of bi-ventricular pacing (right and left ventricles), atri-ventricular pacing mode (simultaneous stimulation by threeelectrodes, with an additional electrode in the right or left cavity),or even multi-ventricular (with multi-electrode leads for which multipleelectrodes of the same lead are used concurrently). By appropriateswitching, the practitioner can choose the most appropriate stimulationmode, but the number of possible configurations increases very rapidlywith the increase of the electrodes, making the task all the moredifficult for the practitioner, faced with a choice between a largenumber of different configurations.

Third, the device should be set properly, including the atrioventriculardelay (AVD) and interventricular delay (VVD).

The many opportunities arising from these various choices are referredto as “pacing configurations.”

Indeed, it appears that today, even with full implementation ofprocedures, there are approximately 30% of patients who do not respondto CRT therapy, with serious consequences that can be imagined in termsof quality of life, hospitalizations for heart failure and reduced lifeexpectancy.

Most studies now focus on methods to treat this refractory patientpopulation by testing new stimulation configurations, and seeking tooptimize the stimulation setting, during the implantation as well as onan ongoing basis, by periodic reassessments.

There is thus a real need for a technique to evaluate, according to asimple, rapid, automated and precise method, the impact of the choice ofthe stimulation sites and of the parameters of CRT therapy, especiallythe AVD and VVD, so as to optimize the patient's hemodynamic status.

The reference technique for the adjustment of CRT stimulation parametersis an assessment by echocardiography with estimation of thecharacteristic delays of the systole, in particular the delay of openingof the aortic valve. This procedure, which must be implemented inhospitals and by qualified personnel, is time consuming and expensiveand cannot be applied as often as would be useful or necessary. Inaddition, it is not easy to perform ultrasound measurements during theimplantation procedure, as the sterile field does not allow easy accessto the patient's chest with the ultrasound probe.

Other techniques have been proposed to evaluate the effectiveness of thechoice of stimulation pacing sites and of the setting of CRT therapyparameters. Thus, EP 1736203 A1 and its US counterpart U.S. Pat. No.7,664,547 (both assigned to Sorin CRM S.A.S, previously known as ELAMedical) describe a CRT device that uses for this purpose the parametersrelated to endocardial acceleration (hereinafter “EA”) to determine anoptimal pacing configuration, at the time of implantation or thereafter.

Indeed, it may be necessary to reassess these choices later, after theinitial implantation, and eventually readjust the settings. The benefitsprovided by CRT therapy can ultimately lead to change the initialconfiguration and setup of the stimulation.

Indeed, several clinical studies have shown that endocardialacceleration is a parameter that accurately and in real-time reflectsphenomena related to the movements of the heart chamber, and cantherefore provide comprehensive information on the mechanical heart,both in the case of normal operation and in the case of a deficientoperation. Endocardial acceleration is for example measured by anaccelerometer integrated into an endocardial lead, as described forexample in EP 0515319 A1 and its US counterpart U.S. Pat. No. 5,304,208(both assigned to Sorin Biomedica Cardio SpA).

WO 2006/049538 A1 (St. Jude Medical AB) describes a known technique toevaluate a physiological parameter that reflects the hemodynamicperformance of the heart for a given stimulation configuration, fromvarious sensors (pressure, acceleration, acoustic) placed on one or moreleads, some of them being possibly repositioned; thus the signaldelivered by these sensors depends on the current position of the leadand cannot be a reliable reference. However, the proposed technique hasa number of drawbacks, including the fact that the optimization is basedon the analysis of a single physiological parameter (e.g., cardiacoutput, stroke volume). However, some patients may be more or lesssensitive to either of these parameters, which is not always the samefrom one patient to another because of the specific response of thepatient, his pathology and the evolution of it. Further, the analyzedparameter is not necessarily the most relevant relatively to the changesin the stimulation configuration.

SUMMARY

It is, therefore, an object of the present invention to propose a systemor apparatus that can help the practitioner find the pacingconfiguration that is the most appropriate, especially to enable thepractitioner to evaluate the effectiveness of modifications to pacingconfigurations due to repositioning of the lead and, where appropriate,selections of additional leads (bi-ventricular, tri-ventricular ormultiventricular pacing) or switching of electrodes in the case of amulti-electrode lead.

It is another object of the present invention to provide a technique forevaluating the pacing configuration with an increased sensitivity andspecificity compared to what has been proposed to date, including the EP1736203 A1 cited above, particularly with respect to changes of positionof the pacing electrodes.

It is another object of the present invention to define indexes ofcardiac hemodynamic performance of the patient, to optimize thepositioning of the leads and the choice of configurations of the CRTpacemaker during the implantation procedure, and the possiblereprogramming of any parameter after the CRT device implantation.

Another object of the present invention is to provide completeequipment, made available to the implanting practitioner, which isspecifically adapted to the selection of stimulation pacing sites duringthe process of implantation of the leads and of a bi-ventricular,tri-ventricular or multi-ventricular device.

To this end, the present invention is broadly directed to a system forseeking an optimal pacing configuration for an active medical device(implantable cardiac prosthesis or external device used temporarily)implementing CRT by bi-, tri- or multiventricular pacing, this systemincluding, as taught by and disclosed in EP 1736203 A1 cited above, towhich one skilled in the art is referred:

-   -   means for ventricular pacing, able to deliver stimulation pacing        pulses to be applied to electrodes located respectively at least        at one right ventricular pacing site and at least at one left        ventricular pacing site according to a predetermined pacing        configuration that is current and modifiable;    -   an acceleration sensor for delivering an endocardial        acceleration (EA) signal representative of cyclical contractions        and relaxations of the heart, and    -   means for isolating and preprocessing in the EA signal during a        given cardiac cycle between two successive ventricular        events: (i) an EA1 component corresponding to the first peak of        endocardial acceleration associated with the isovolumetric        ventricular contraction, and (ii) an EA2 component corresponding        to the second peak of endocardial acceleration associated with        the isovolumetric ventricular relaxation.

It is another aspect of the present invention to assess the efficiencyof stimulation based on a “performance index” compiled from parametersfrom a signal delivered by an endocardial acceleration sensor,including: the amplitude of the first endocardial acceleration peak, theduration of this peak, and the duration of systole (i.e., the intervalbetween the first and second peaks of endocardial acceleration).

Preferably, a system in accordance with the present invention furtherincludes means for evaluating the effectiveness of the current pacingconfiguration, including:

-   -   means for extracting at least two parameters from the isolated        and preprocessed EA1 and EA2 components:        -   means for combining said at least two parameters in a            composite index representative of the effectiveness of that            current pacing configuration;        -   means for determining a plurality of values of said            composite index for a corresponding plurality of different            pacing configurations, and        -   means for determining a preferred pacing configuration from            said plurality of values of said composite index by            searching for an optimum of that composite index.

In a preferred embodiment, said at least two parameters characteristicof the EA1 and EA2 components are parameters selected from among thegroup consisting of:

-   -   PEA1=value of the peak-to-peak EA1 component;    -   TstEA1=duration of occurrence of the beginning of the EA1        component represented by the time interval between i) a temporal        marker of the beginning of the cardiac cycle and ii) the        crossing of an energy envelope threshold of the EA1 component;    -   LargEA1=time interval between i) said crossing of the energy        envelope threshold, and ii) the instant of the peak of said        energy envelope of the EA1 component; and    -   Syst=duration of systole, represented by the time interval        between the beginning of the EA1 component and the beginning of        the EA2 component.

In one embodiment, the composite index is an index selected from amongthe group consisting of:

Ind1=(TstEA1×LargEA1)/(Syst×PEA1);

Ind2=(TstEA1×LargEA1)/[(Syst−LargEA1)×PEA];

Ind3=(TstEA1×LargEA1)/(Syst); and/or

Ind4=(TstEA1)/(PEA1),

said optimum being a minimum of the indexes.

The system advantageously comprises an atrial lead carrying theendocardial acceleration sensor, and left and right ventricular leadswith their distal electrode respectively defining the pacing site(s) forright and left ventricular pacing according to the current pacingconfiguration. It may also include an additional, right or left,ventricular lead carrying at its distal end electrodes for definition ofat least one additional pacing site for ventricular pacing, defining thecurrent pacing configuration in combination with the right and leftventricular pacing site(s).

Another embodiment of the present invention is directed to a systemincluding:

-   -   An implantable active medical device capable of delivering CRT        by bi-, tri- or multi-ventricular stimulation;    -   An atrial lead carrying an endocardial acceleration sensor;    -   Right and left ventricular leads respectively carrying distal        electrodes for definition of the right and left ventricular        pacing sites according to a current pacing configuration;    -   Optionally an additional, right or left, ventricular lead        carrying at its distal end electrodes for definition of at least        one additional ventricular pacing site, defining the current        pacing configuration in combination with the right and left        ventricular pacing site(s);    -   An external device for providing cardiac detection/stimulation        for a patient;    -   An interface unit comprising means for processing an EA signal,        provided by said EA sensor, and means for coupling the external        equipment to the atrial and ventricular leads; and    -   External programmer means, coupled to the interface housing for        reception of the processed EA signal, including the means for        evaluating the effectiveness of the pacing configuration.

One embodiment relates to a memory device having instructions storedthereon that, when executed by a processor of an implantable medicaldevice, cause the implantable medical device to perform operations. Theoperations include generating, using an acceleration sensor of theimplantable medical device, an endocardial acceleration (EA) signalrepresentative of activity of a patient's heart. The operations furtherinclude identifying within the EA signal a first EA signal componentcorresponding to a first peak of endocardial acceleration and a secondEA signal component corresponding to a second peak of endocardialacceleration. The operations also include extracting from at least oneof the first EA signal component and the second EA signal component atleast two characteristic parameters, the at least two characteristicparameters relating to at least two different types of characteristicsof the at least one of the first EA signal component and the second EAsignal component. The at least two different types of characteristics towhich the at least two characteristic parameters relate are selectedfrom among the following:

-   -   a peak-to-peak amplitude (PEA1) of the first EA signal        component;    -   a first time interval (TstEA1) between a beginning of a cardiac        cycle and a beginning of the first EA signal component;    -   a second time interval (LargEA1) between the beginning of the        first EA signal component and a peak associated with the first        EA signal component; or    -   a third time interval (Syst) representative of a duration of a        systole, the third time interval between the beginning of the        first EA signal component and a beginning of the second EA        signal component.        The operations may further include generating a composite index        based on a combination of the at least two characteristic        parameters, wherein the composite index is selected from among        the following:

Ind1=(TstEA1×LargEA1)/(Syst×PEA1);

Ind2=(TstEA1×LargEA1)/[(Syst−LargEA1)×PEA1];

Ind3=(TstEA1×LargEA1)/(Syst); or

Ind4=(TstEA1)/(PEA1);

The operations may further include determining a plurality of values ofthe composite index for a plurality of pacing configurations. Theoperations may further include selecting a current pacing configurationfor the implantable medical device from among the plurality of pacingconfigurations based on the plurality of values of the composite index.

DRAWINGS

FIG. 1 is a series of three timing diagrams illustrating various signalscharacterizing the cardiac activity during a given cycle;

FIG. 2 illustrates, in more detail, the shape of the endocardialacceleration signal during a given cardiac cycle, with the variousparameters used for the implementation of the invention;

FIG. 3 schematically illustrates the various elements of a preferredembodiment of the present invention in the form of functional blockdiagrams, of the equipment available to the practitioner at the time ofimplantation for the selection of the pacing sites of the invention;

FIG. 4 illustrates a diagram displayed by the interface of FIG. 3 forselection of the pacing sites;

FIG. 5 is a flow chart describing the various stages of a preferredmethod of implementing the elements of the present invention; and

FIG. 6 is a flow chart describing the various stages of the long-termpatient's monitoring by analysis of the evolution of one or more of theindexes calculated according to a preferred embodiment of the presentinvention.

DETAILED DESCRIPTION

With reference to the drawing FIGS. 1-6, a preferred embodiment of anapparatus according to the present invention will now be described.

The present invention may particularly be applied to active implantablemedical devices such as those of the Paradym CRT device family producedand marketed by Sorin CRM, Clamart France, formerly known as ELAMedical, Montrouge, France. These devices include programmablemicroprocessor circuitry to receive, format, and process electricalsignals collected (detected) by electrodes implanted in a patient, anddeliver stimulation pulses to these electrodes. It is possible totransmit by telemetry software that will be stored in a memory of theimplantable devices and executed to implement the functions of theinvention that will be described herein. The adaptation of these devicesto implement the functions and features of the present invention isbelieved to be within the abilities of a person of ordinary skill in theart, and therefore will not be described in detail.

The technique of the present invention is based on the analysis ofendocardial acceleration (hereinafter “EA”), which is a parameter thataccurately and in real time reflects the phenomena contributing to themechanical operation of the myocardium and may be measured by anaccelerometer coupled to the heart muscle, as described for example inEP 0515319 A1 (and its counterpart: U.S. Pat. No. 5,304,208) (SorinBiomedica Cardio SpA). This document teaches a method to collect an EAsignal through an endocardial lead equipped with a distal stimulationelectrode implanted in the atrium or ventricle and integrating amicroaccelerometer to measure endocardial acceleration.

Note however that, although in the present description it is referredmainly to the analysis of an EA signal delivered by a sensor placed onan endocardial lead, the invention is also applicable to an analysisconducted from an EA signal delivered by other types of implantedsensors, such as a myocardium wall motion sensor, an epicardial sensoror an accelerometer placed in the case of an implant. The invention isalso applicable to the analysis of a noninvasively collected external EAsignal, e.g., from a sensor attached to the patient's chest at thesternum.

FIG. 1 shows the different signals characterizing the activity of apatient's heart during a cardiac cycle, with: the profile ofintracardiac pressures (P_(A), P_(VG) and P_(OG)), a record of surfaceelectrocardiogram (ECG), and the variations of the endocardiacacceleration (EA) signal. The characteristic P_(A) shows the variationsin the aortic pressure, P_(VG) in the left ventricular pressure andP_(OG) in the left atrium pressure. Points A to E correspond to thedifferent following phases: A contraction of the left atrium, B closureof the mitral valve, C opening of the aortic valve, D closure of theaortic valve, E opening of the mitral valve. The ECG signal hassuccessively the P wave corresponding to the depolarization of theatria, the QRS complex corresponding to the depolarization of theventricles, and the T wave corresponding to the ventricularrepolarization.

The EA signal collected during a given cardiac cycle forms two maincomponents, corresponding to the two major heart sounds (S1 and S2sounds of phonocardiogram) that can be recognized in each cardiac cycle:

-   -   the EA1 component, starting after the QRS complex is caused by a        combination of the closure of the atrioventricular valves, the        opening of the semilunar valves and the contraction of the left        ventricle. The amplitude variations of this EA1 component are        closely related to the changes in pressure in the ventricle (the        maximum peak to peak amplitude being specifically correlated        with the positive maximum of dP/dt pressure variation in the        left ventricle) and thus can provide a parameter representative        of the myocardium contractility, which is itself linked to the        level of activity of the sympathetic system; and    -   the EA2 component occurs during the phase of isovolumetric        ventricular relaxation. It accompanies the end of ventricular        systole and is mainly produced by the closure of the aortic and        pulmonary valves.

For one implementation of the present invention, it is first necessaryto extract from the EA signal, the endocardial acceleration and morespecifically the two components EA1 and EA2, characteristics correlatedwith time intervals of the systole and to other myocardium hemodynamicperformance indexes, by specific processing of this EA signal.

The preliminary processing of the EA components preferably involves,first, to individualize the successive cardiac cycles in the EA signalthat is continuously collected, identifying markers of the beginning ofthe cycle to separate these cycles and isolate a series of EAsub-signals bounded in time, each corresponding to a period of onecardiac cycle.

In the case of an endocardial EA signal, the time markers of thebeginning of the cycle may be provided by the implant itself or by anexternal device during implantation, which according to the mode storesthe timings of V pacing, or the timings of R-wave detection. Thetemporal marker of the beginning of the cycle, which is the origin oftime, is designated “O”.

The next step is to isolate the EA1 and EA2 components in eachsub-signal bounded in time corresponding to one cardiac cycle. Each ofthese EA1 and EA2 components are represented by a set of successivevalues describing the continuous variation of the EA signal in a giventime window extending around the peak of the EA signal (PEA1 peak orPEA2 peak), for a fraction of the duration of a cardiac cycle.Specifically, each component consists of a subset of the EA signalsamples obtained after digitization of this signal over the duration ofthe cardiac cycle.

Each of these components represents a fraction of the EA signal on theduration of a cardiac cycle, each cardiac cycle comprising a pluralityof different components that occur in succession, including the firsttwo components EA1 and EA2, which are followed by secondary componentsknown in the art as EA3 and EA4.

Preferably, the EA1 and EA2 components of the signal EA are determinedwith an averaging over several cycles, typically three to five cycles,using a technique such as that described in EP 2092885 A1 (and itscounterpart: US Patent Publication No. 2009/0209875) (both assigned toSorin CRM S.A.S., previously known as ELA Medical), a technique thatallows including the elimination of the cycle to cycle variations by atime readjustment of the successive components before averaging.

Essentially, this technique is to perform a preprocessing of the EAsignal continuously collected, with:

-   -   Division of the EA signal into sub-signals each corresponding to        the duration of one cardiac cycle and identified by a marker of        cycle beginning to achieve this division;    -   Segmentation of each of these sub-signals in order to        individualize the EA1 and EA2 components in a given temporal        window;    -   For the current EA1 or EA2 component thus isolated on a cycle,        seeking for a cross-correlation peak with respect to the EA1 (or        EA2) components from the other collected cycles;    -   Calculation of a corresponding temporal shift; and    -   Application of the temporal shift thus calculated to the current        component, so as to align it with the others.

The analysis processing can then be performed on these successive EA1and EA2 components, with elimination of the bias of the cycle to cyclevariability as a result of the preprocessing.

In one embodiment, the present invention is based on the extraction andanalysis of a number of characteristic parameters of the EA1 and EA2components, parameters which are then combined to give composite indexesthat the practitioner seeks to optimize (minimize or maximize dependingon the cases), the reached optimum reflecting the best pacingconfiguration among all those that have been tested.

These parameters are four in number, and are illustrated in FIG. 2 whichshows the variation of the EA signal during one cardiac cycle, with itstwo EA1 and EA2 components.

-   -   The peak-to-peak component EA1, designated PEA1;    -   The timing of the beginning of the EA1 component, denoted        TstEA1, which is a period counted from the time origin O in FIG.        2;    -   An indicator of the duration of the EA1 component, designated        LargEA1, which is the time interval between the instant TstEA1        from the instant t_(maxEA1energy) of the energy peak of the EA1        component; and    -   The duration of systole, designated Syst, corresponding to the        time interval between TstEA1, which marks the beginning of the        EA1 component, and TstEA2, which marks the beginning of the EA2        component.

The timings TstEA1 and TstEA2 of start of the EA1 and EA2 components canbe obtained by thresholding an envelope of energy obtained by squaringthe value of the signal samples (envelope shown in dashed lines in FIG.2), then applying a smoothing window of 100 ms, for example. The timingsTstEA1 and TstEA2 correspond to a threshold that can be for example 10%of the maximum energy of the considered window corresponding to the oneand the other of two EA1 and EA2 components.

The respective timings of occurrence of the maximum energy of the EA1and EA2 components, denoted t_(maxEA1energy) and t_(maxEA2energy), areused to calculate in particular the LargEA1=t_(maxEA1energy)−TstEA1.

This method for determining characteristic instants of the EA1 and EA2components is described as well as others in EP 2092885 A1 and itscounterpart US Patent Publication No. 2009/0209875 cited above, whichcan be referred for more details and are incorporated herein byreference in their entirety.

The above parameters are chosen for the following reasons:

-   -   the PEA1 amplitude is associated with the cardiac contractility        (clinical studies have shown a strong correlation with the        maximum LVdP/dT). Effective stimulation for an optimal position        of the pacing electrode, has the effect of maximizing this        parameter.    -   The timing of occurrence of the beginning of the EA1 component        TstEA1 is associated with the phase of isovolumetric contraction        of the cardiac cycle, particularly at the instant of opening of        the aortic valve, timing also known as “Left Pre-Ejection        Interval”, LPEI. Clinical studies suggest that minimization of        this parameter reflects an improvement in ventricular        resynchronization and hemodynamic performance. It can also be        found that this parameter is also very sensitive to changes in        position of the electrodes of the lead.    -   The duration LargEA1 is a good indicator of the        resynchronization. Reduced values should be sought for the        duration of this value. It was also found that this parameter is        much more sensitive to changes in the positions of the        electrodes, in particular, the full length of the EA1 component        (time interval between the beginning and the end of the EA1        component). It is also more reliable than a technique of using        the instant of the end of the EA component by detecting it by        thresholding and averaging over several cycles: a relatively        high variability is then found compared to the moment the peak        is reached.    -   The duration of systole Syst is associated with the time between        the closure of the mitral valve and that of the aortic valve.        This parameter gives a good indication of the performance of the        ejection phase. This parameter is also very sensitive to changes        in position of the electrodes.

In other words, the above four parameters have a particularly highsensitivity and accuracy in response to changes in pacingconfigurations, which very effectively guides the practitioner in theselection and adjustment of the pacing sites.

These parameters are also sensitive to the pacemaker settings (includingAVD and VVD delays), and may be used for initial adjustment or laterreadjustment.

However, the optimization of one of the four above parameters is notalways sufficient to determine with certainty the best pacingconfiguration and the best settings of the device. The use of a singleparameter in fact leads to an excessive number of incorrectdeterminations, which is why the present invention proposes to combine aplurality of these parameters (at least two) in one or more indexescalled “composite indexes” to reliably determine the best choice ofpacing configuration.

The following composite indexes were chosen because they are all verysensitive to changes in position of the pacing sites:

Ind1=(TstEA1×LargEA1)/(Syst×PEA1):

This index combines the various characteristic durations of the cardiaccycle and the parameters reflecting contractility, and has the highestsensitivity to changes in the position of the pacing sites and the bestcorrelation with the clinical references;

Ind2=(TstEA1×LargEA1)/[(Syst−LargEA1)×PEA1]:

This index is very similar to the previous one, but the differenceSyst−LargEA1 enables more stability in the factor related to theduration of systole;

Ind3=(TstEA1×LargEA1)/(Syst):

This index is derived from the first one, without contribution ofcontractility and is more suitable for applications in whichoptimization is strictly related to the timings of the cardiac cycle andis not or is little dependent of contractility;

Ind4=(TstEA1)/(PEA1):

This index is a subsidiary index and reflects cardiac performance whenoptimization is only those of the phase of ventricular contraction. Itcan particularly be used if the closure of the aortic valve is difficultto detect (that is, when the EA2 component is hardly visible), leadingto an uncertain determination of the duration of systole Syst, becauseof an unreliable signal related to the relaxation phase of the cardiaccycle.

For all these indexes, the optimum to seek is the minimum.

The composite indexes above have proved to be very effective in clinicalstudies, and adapted to many different hemodynamic conditions ofpatients, for various pathologies.

This list is not exhaustive, and persons having ordinary skill in theart would understand that other combinations of the parameters listedabove can be used in other situations or particular pathologies.

A preferred method to achieve, in practice, an optimization inaccordance with the present invention during the implantation phase,with reference to FIGS. 3-5, will now be described.

FIG. 3 schematically shows the facility used to optimize the position ofthe pacing sites and of the programmed parameter configurations. Thesystem includes a CRT pacemaker and/or resynchronizer implantablemedical device 10, provided with a plurality of leads implanted in theheart with a right atrial lead RA, referenced 12, equipped at its distalend with an EA sensor, e.g., an accelerometer for delivering an EAsignal 14. Note that the EA sensor is placed on an atrial lead, which istherefore another lead than those to be displaced to find an optimalpacing configuration. In other words, the lead on which the EA sensor isplaced is not involved in the definition of the “pacing configuration”in the sense described above.

The device is also connected to right ventricular RV and leftventricular LV leads, referenced 16, 18, and possibly to an additionalventricular lead V+, referenced 20, which can be used to improve theventricular performances, especially if pacing by the RV and LV leaddoes not provide sufficient improvement in hemodynamics.

These leads are directly connected to the generator 10 and temporarily,via sterile cables, to an interface unit 22 for seeking of the optimalpacing configuration.

The ventricular lead may also be, as shown in 20′ on the variation inthe lower right heart scheme, a ventricular right or left“multi-electrode” lead. The EP 1938861 A1 (and counterpart: U.S. PatentPublication No. 2008/0177343) and EP 2082684 A1 (and counterpart: USPatent Publication No. 2009/0192572) (both on behalf of Sorin CRMS.A.S., previously known as ELA Medical) describe such a lead having aplurality of electrodes near its distal end, for example, tenelectrodes, associated with a chip, hermetically encapsulated in thevicinity of the electrodes in a rigid ring, providing themultiplexing/demultiplexing of the electrodes with a common bus havingtwo insulated conductors extending along the entire length of the leadto the proximal connector for coupling with the generator, the latterbeing equipped with a counterpart circuit fordemultiplexing/multiplexing.

The interface housing 22 includes a proper interface 24 for receivingsignals from the electrodes RA, RV, LV and V+, or delivery of pacingpulses on these same conductors. A stage 26 is used to filter andamplify the various detected depolarization signals and the EA signal. Amultiplexer 28 also selectively ensures switching of the variousconductors with a Pacemaker System Analyzer (“PSA”) or temporary pacingsystem 30 for external stimulation, possibly included in the interfaceunit 22, designed to continuously ensure functions of detection andgeneration of stimulation pulses during testing of the differentconfigurations, in relay of the implanted generator 10 or beforeconnecting it to the leads 12, 16, 18 and 20.

The system also includes a programmer 40 or another computer system,comprising a software module for the acquisition and processing of EAand cardiac depolarization signals, particularly for calculating one ormore of the composite indexes Ind1 to Ind4, in accordance with thepresent invention. This programmer 40 includes a processing unit 42, ameasurement unit 44 and a storage memory 46. It can possibly be expectedto include a keyboard 48 or other conventional means of data entry.

Finally, a display 50 allows the practitioner to present the variousoptions available to him to define the various pacing configurations.The display can take the form shown in FIG. 4, with a schematicrepresentation of the different regions of the heart identifying the keytargets:

-   -   For the right atrium RA: atrial appendage AA, lateral wall LW        and atrial septum AS;    -   For the right ventricle RV: output flow track region OFT, low        septum LS, medium and high septum, MS and HS, and bottom APEX;    -   For the coronary system CS (by which the left ventricle is        stimulated): great cardiac vein GCV, lateral vein LV,        posterolateral vein PLV, posterior vein PV and middle cardiac        vein MCV.

FIG. 5 shows an example of a preferred method in accordance with thepresent invention for the selection of the best pacing configuration atthe time of implantation. After the various initializations (step 100),the practitioner checks the configurations to be tested (step 102). Thereference condition which is then used for the various comparisons canbe that corresponding to the particular patient's spontaneous rhythm inorder to allow the spontaneous rhythm be expressed (step 104). Forsafety, the external stimulator (PSA) is normally disconnected from thelead; it is connected only for the later steps of testing the variouspacing configurations.

The detection thresholds for synchronization of the sensor signals arealso determined during this initial phase (step 106).

The external generator (PSA) is then connected, stimulation is appliedand various checks are performed, including the stability of the rhythm(step 108).

An initial configuration is then tested (step 110), the EA signalprocessing producing (block 112) the sought composite indexes Ind1,Ind2, Ind3 and/or Ind4 (it should be understood however, that obtainingtwo of these indexes is usually sufficient).

Other pacing configurations are then tested with different electrodeswitching (step 114). Note that the setting of the AVD and VVD isgenerally not changed at this step (rather they are changed at a laterstep of possible optimization after site selection and monitoring of thepatient). It may in particular be programmed with a short AVD selectedin the range from 80 to 100 ms, and a VVD equal to zero.

The corresponding indexes are evaluated (block 116) and compared withthe reference indexes, to give an overall result (step 118).

The practitioner can then change the location of the leads or repositionthem (block 120) and repeat the process described above (back to step100), to again give new results in step 118.

The successive results obtained are compared in order to determine thepacing configuration providing the optimal efficiency. For example, thepractitioner can test various configurations. The first set of testconfigurations is a “standard” set including:

-   -   Spontaneous rhythm (as reference);    -   Stimulation of the right ventricle RV alone (for purposes of        diagnosis or as a reference configuration);    -   Stimulation of the left ventricle only;    -   Conventional bi-ventricular pacing (which can also be chosen as        the reference configuration), with concomitant stimulation of        both right and left ventricles RV-LV.

The diagnosis is used to evaluate the sensitivity of the indexes in theworst conditions of stimulation, for a patient with heart failure; it isnot, however, to consider such stimulation as a possible programmablepacing configuration.

Then, all possible configurations involving repositioning the lead orthe addition of an additional lead V+ are tested. The repositioning ofthe RV and LV leads involves repeating the test for basic configurationsRV only, LV only, and RV-LV. Adding an additional lead V+ to stimulatethe left or right ventricle involves testing all possible pacingcombinations:

-   -   Bi-ventricular (concomitant stimulation LV−V+ or RV−V+),    -   Tri-ventricular pacing (concomitant stimulation V+, RV and LV),    -   Multi-ventricular pacing (concomitant stimulation on several        electrodes of a multielectrode lead, and on RV and LV).

The configuration in spontaneous rhythm is always reassessed at thebeginning of each series of tests, and indexes are compared with thoseobtained the first time (reference configuration). If a substantialvariation of the index in the spontaneous condition is established, awarning is displayed, and the practitioner should check the patient'scondition: indeed, a change in the index should not normally occur,otherwise it is a symptom of deterioration of the patient, to be takeninto account immediately.

The practitioner can for example test the following three sets ofconfigurations shown in the following table:

Configurations to be tested (new or Configurations Implanted leadBrought changes modified) n^(o)1 RA, RV, LV — Spontaneous, LV only, BiVn^(o)2 RA, RV, LV RV repositioning Spontaneous, BiV n^(o)3 RA, RV, V+,V+ added Spontaneous, BiV+, LV TriV

Of all the tested configurations, the one that is selected is the onethat produces the optimal of the composite index(s) (the minimum valuewith the indexes Ind1 to Ind4 exemplified above).

Later, after the stimulation pacing sites have been selected, acomparable analysis algorithm can be implemented to test configurationsdiffering in the settings of the AVD and/or the VVD to maximize thevalues of these parameters. It may be the same after implantation in thepatient follow-up, in order to assess the impact of a change in thepacing configuration and/or in the setting of the AVD and VVD.

It is thus possible to calculate the indexes for each pair of values{AVD, VVD}, then to choose the pair that is associated with the highestindex value. The analysis can be done by trying to optimize thecomposite indexes Ind1, Ind2, Ind3 and/or Ind4 described above (theoptimization typically is on two of these indexes).

It is also possible to use the indexes to monitor the patient'spathology in the long term, in order to assess the deleterious effectsof remodeling and prevent the occurrence of an adverse event resultingfrom the increase of the heart failure status. It is then to assess theevolution over time of a given index to detect a deterioration in thepatient's condition and send a warning to the practitioner, for example,to change the therapy (optimized pacing configuration, change in thesettings of AVD and VVD, medication, etc.).

FIG. 6 outlines the various steps of such a patient follow-up on thelong-term by analysis of the evolution of one or more of the indexesInd1, Ind2, Ind3 and/or Ind4 described above. For example, for acontinuous follow-up of the patient's status, the first step involvescomputing of indexes several times a day (3-4 times), while the patientis at rest. Next, computing of the same indexes occurs during exercise(if available). This is followed by detection of any increase/decreaseof the index trend on “N” successive days (for example: N=7 days),followed by a comparison (i) to a threshold (min/max) of the variationsof the index slope, (ii) of spontaneous rhythm indexes vs. ventricularpacing indexes, and (iii) of indexes at rest vs. at exercise. A test isthen performed as to whether a sudden variation of the series of indexvalues is detected. If yes, then an alert is given to the physician forpatient examination; and if no then a test is performed as to whetherthere is significant change during time of the series of index valuesdetected. If the result of the latter test is yes, then an alert is sentto physician for patient examination; and otherwise the routine returnsto the initial step of computing of indexes several times a day (3-4times), while the patient is at rest).

One skilled in the art will understand the present invention is notlimited by, and may be practice by other than the foregoing embodimentsdescribed, which are presented for purposes of illustration and not oflimitation.

1. An implantable medical device comprising: a sensor configured togenerate an endocardial acceleration (EA) signal representative ofactivity of a patient's heart; one or more circuits configured to:identify within the EA signal at least one EA signal componentcorresponding to at least one predetermined portion of the EA signal;extract from the at least one EA signal component at least twocharacteristic parameters, the at least two characteristic parametersrelating to at least two different types of characteristics of the atleast one EA signal component; generate a composite index based on acombination of the at least two characteristic parameters; determine aplurality of values of the composite index for a plurality of pacingconfigurations; and select a current pacing configuration from among theplurality of pacing configurations based on the plurality of values ofthe composite index.
 2. The device of claim 1, wherein the one or morecircuits are configured to identify within the EA signal a first EAsignal component corresponding to a first predetermined portion of theEA signal and a second EA signal component corresponding to a secondpredetermined portion of the EA signal.
 3. The device of claim 2,wherein the one or more circuits are configured to isolate and processin the EA signal the first EA signal component and the second EA signalcomponent during one cardiac cycle between two successive ventricularevents, wherein the first EA signal component corresponds to the firstpredetermined portion of the EA signal associated with an isovolumetricventricular contraction, and wherein the second EA signal componentcorresponds to the second predetermined portion of the EA signalassociated with an isovolumetric ventricular relaxation.
 4. The deviceof claim 2, wherein the one or more circuits are further configured todeliver pacing pulses to be applied to electrodes configured to belocated at at least one right ventricular pacing site and at least oneleft ventricular pacing site in a modifiable pacing configuration. 5.The device of claim 2, wherein the at least two different types ofcharacteristics to which the at least two characteristic parametersrelate are selected from among the following: a peak-to-peak amplitude(PEA1) of the first EA signal component; a first time interval (TstEA1)between a beginning of a cardiac cycle and a beginning of the first EAsignal component; a second time interval (LargEA1) between the beginningof the first EA signal component and a peak associated with the first EAsignal component; or a third time interval (Syst) representative of aduration of a systole, the third time interval between the beginning ofthe first EA signal component and a beginning of the second EA signalcomponent.
 6. The device of claim 5, wherein at least one of thebeginning of the first EA signal component or the beginning of thesecond EA signal component comprises a time at which an energy envelopeof the respective EA signal component exceeds a threshold value.
 7. Thedevice of claim 5, wherein the at least one electronic circuit isconfigured to generate the composite index based on the TstEA1.
 8. Thedevice of claim 7, wherein the at least one electronic circuit isconfigured to generate the composite index based on a combination of theTstEA1 and the LargEA1.
 9. The device of claim 8, wherein the at leastone electronic circuit is configured to generate the composite indexbased on a combination of the TstEA1, the LargEA1, and the Syst.
 10. Thedevice of claim 9, wherein the composite index comprises a compositeindexInd1=(TstEA1×LargEA1)/(Syst×PEA1).
 11. The device of claim 9, whereinthe composite index comprises a composite indexInd2=(TstEA1×LargEA1)/[(Syst−LargEA1)×PEA1].
 12. The device of claim 9,wherein the composite index comprises a composite indexInd3=(TstEA1×LargEA1)/(Syst).
 13. The device of claim 7, wherein thecomposite index comprises a composite indexInd4=(TstEA1)/(PEA1).
 14. The device of claim 1, wherein the at leastone electronic circuit is configured to select the current pacingconfiguration associated with a lowest value or a highest value of theplurality of values of the composite index.
 15. The device of claim 1,further comprising: an atrial lead carrying the sensor; a rightventricular lead carrying a first distal electrode configured to beplaced in one or more positions within a right ventricle in theplurality of pacing configurations; and a left ventricular lead carryinga second distal electrode configured to be placed in one or morepositions within a left ventricle in the plurality of pacingconfigurations.
 16. The device of claim 1, wherein the one or morecircuits are configured to transmit data relating to one or more of theplurality of values of the composite index to an external programmingdevice configured to assess an effectiveness of one or more of theplurality of pacing configurations based on the one or more of theplurality of values of the composite index.
 17. The device of claim 1,wherein the at least one predetermined portion of the EA signalcomprises a peak of endocardial acceleration.
 18. A method comprising:generating, using an acceleration sensor of an implantable medicaldevice, an endocardial acceleration (EA) signal representative ofactivity of a patient's heart; identifying within the EA signal a firstEA signal component corresponding to a first predetermined portion ofthe EA signal and a second EA signal component corresponding to a secondpredetermined portion of the EA signal; extracting from at least one ofthe first EA signal component and the second EA signal component atleast two characteristic parameters, the at least two characteristicparameters relating to at least two different types of characteristicsof the at least one of the first EA signal component and the second EAsignal component; generating a composite index based on a combination ofthe at least two characteristic parameters; determining a plurality ofvalues of the composite index for a plurality of pacing configurations;and selecting a current pacing configuration for the implantable medicaldevice from among the plurality of pacing configurations based on theplurality of values of the composite index.
 19. The method of claim 18,wherein identifying the first EA signal component and the second EAsignal component comprises isolating and processing in the EA signal thefirst EA signal component and the second EA signal component during onecardiac cycle between two successive ventricular events, wherein thefirst EA signal component corresponds to the first predetermined portionof the EA signal associated with an isovolumetric ventricularcontraction, and wherein the second EA signal component corresponds tothe second predetermined portion of the EA signal associated with anisovolumetric ventricular relaxation.
 20. The method of claim 18,wherein the at least two different types of characteristics to which theat least two characteristic parameters relate are selected from amongthe following: a peak-to-peak amplitude (PEA1) of the first EA signalcomponent; a first time interval (TstEA1) between a beginning of acardiac cycle and a beginning of the first EA signal component; a secondtime interval (LargEA1) between the beginning of the first EA signalcomponent and a peak associated with the first EA signal component; or athird time interval (Syst) representative of a duration of a systole,the third time interval between the beginning of the first EA signalcomponent and a beginning of the second EA signal component.
 21. Themethod of claim 20, wherein the at least one electronic circuit isconfigured to generate the composite index based on the TstEA1.
 22. Themethod of claim 21, wherein the at least one electronic circuit isconfigured to generate the composite index based on a combination of theTstEA1 and the LargEA1.
 23. The method of claim 22, wherein the at leastone electronic circuit is configured to generate the composite indexbased on a combination of the TstEA1, the LargEA1, and the Syst.
 24. Themethod of claim 23, wherein the composite index comprises one of thefollowing composite indexes:Ind1=(TstEA1×LargEA1)/(Syst×PEA1);Ind2=(TstEA1×LargEA1)/[(Syst−LargEA1)×PEA1]; orInd3=(TstEA1×LargEA1)/(Syst).
 25. The method of claim 21, wherein thecomposite index comprises a composite indexInd4=(TstEA1)/(PEA1).
 26. The method of claim 18, wherein the selectedcurrent pacing configuration is associated with a lowest value or ahighest value of the plurality of values of the composite index.
 27. Amemory device having instructions stored thereon that, when executed bya processor of an implantable medical device, cause the implantablemedical device to perform operations comprising: generating, using anacceleration sensor of the implantable medical device, an endocardialacceleration (EA) signal representative of activity of a patient'sheart; identifying within the EA signal a first EA signal componentcorresponding to a first predetermined portion of the EA signal and asecond EA signal component corresponding to a second predeterminedportion of the EA signal; extracting from at least one of the first EAsignal component and the second EA signal component at least twocharacteristic parameters, the at least two characteristic parametersrelating to at least two different types of characteristics of the atleast one of the first EA signal component and the second EA signalcomponent, wherein the at least two different types of characteristicsto which the at least two characteristic parameters relate are selectedfrom among the following: a peak-to-peak amplitude (PEA1) of the firstEA signal component; a first time interval (TstEA1) between a beginningof a cardiac cycle and a beginning of the first EA signal component; asecond time interval (LargEA1) between the beginning of the first EAsignal component and a peak associated with the first EA signalcomponent; or a third time interval (Syst) representative of a durationof a systole, the third time interval between the beginning of the firstEA signal component and a beginning of the second EA signal component;generating a composite index based on a combination of the at least twocharacteristic parameters, wherein the composite index is selected fromamong the following:Ind1=(TstEA1×LargEA1)/(Syst×PEA1);Ind2=(TstEA1×LargEA1)/[(Syst−LargEA1)×PEA1];Ind3=(TstEA1×LargEA1)/(Syst); orInd4=(TstEA1)/(PEA1); determining a plurality of values of the compositeindex for a plurality of pacing configurations; and selecting a currentpacing configuration for the implantable medical device from among theplurality of pacing configurations based on the plurality of values ofthe composite index.